Chronic reflux is closely associated with the development of adenocarcinoma of the esophagus, which is highly lethal and has one of the fastest rising incidence rates in the United States. Reflux injury replaces squamous epithelium in the esophagus by a pre-malignant, metaplastic columnar epithelium known as Barrett's esophagus. The therapeutic options for adenocarcinoma in Barrett's esophagus are limited and are associated with significant morbidity. The LONGTERM GOAL of our lab is to characterize the molecular mechanisms of carcinogenesis in Barrett's mucosa in order to develop safe, mechanism-based chemopreventive strategies. The esophageal refluxate contains carcinogenic bile salts that are known to activate prostaglandin E2 (PGE2) biosynthesis in Barrett's esophagus. We and others have noted that high levels of PGE2 promote carcinogenesis in Barrett's esophagus. However, the details of the underlying molecular mechanisms remain unclear. The nuclear factor-kappaB (NF-kB) is a survival factor. It is involved in the transcriptional regulation of cyclooxygenase-2, which is the key catalytic enzyme in PGE2 biosynthesis. We made the novel observations that during carcinogenesis there is a constitutive activation of NF-kB in Barrett's mucosa. We also found that NF-kB inhibition in the animal model of esophageal adenocarcinoma markedly decrease PGE2 production in Barrett's mucosa. Using Barrett's epithelial cell cultures we noted that the loss of NF-kB activation can inhibit PGE2 biosynthesis, decrease proliferation and result in increased apoptosis of Barrett's epithelial cells. The significance of this signaling in the development of esophageal adenocarcinoma needs to be further characterized. Based on these observations, we formulated the CENTRAL HYPOTHESIS that the down-regulation of constitutive NF-kB activation, which results in inhibition of PGE2 production, will prevent the development of adenocarcinoma in Barrett's mucosa. The aim of this study is to conduct focused experiments to further understand the importance of constitutive NF-kB activation in reflux induced esophageal adenocarcinoma. We will also examine if the association of NF-kB activation and the development of esophageal adenocarcinoma is PGE2 dependent. To address this, we will use an established animal model of Barrett's esophagus and adenocarcinoma. We will treat the first group of animals with an NF-kB inhibitor (by preventing 1-KB phosphorylation), the second group with NF- inhibitor plus Dimethyl PGE2 and the third group with vehicle only. We will compare the rate of esophageal adenocarcinoma among the treatment groups and assess if the PGE2 levels in Barrett's mucosa influence the effect of NF-kB inhibition on the rate of development of esophageal adenocarcinoma. A successful outcome of this study will broaden our understanding of mechanisms of carcinogenesis in Barrett's mucosa and help define new chemopreventive targets. Moreover, the information obtained from this study may help us understand the mechanisms involved in chronic injury-related cancers elsewhere in the body. [unreadable] [unreadable] [unreadable]